The histamine H3 receptor is primarily expressed in the mammalian central nervous system (CNS), with some minimal expression in peripheral tissues such as vascular smooth muscle. Several indications for histamine H3 antagonists and inverse agonists have been proposed based on animal pharmacology and other experiments with known histamine H3 antagonists (e.g. thioperamide). (See: “The Histamine H3 Receptor-A Target for New Drugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000, 408, 860-864.) These include conditions such as cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
Compounds that possess histamine H3 receptor activity and serotonin transporter (SERT) activity may be useful in the treatment of SERT-mediated disorders such as substance abuse disorders and sexual dysfunction (including premature ejaculation), and particularly beneficial in the treatment of depression. Activation of the H3 receptor on neurons by histamine or an agonist decreases the release of several neurotransmitters including noradrenaline and serotonin, key neurotransmitters involved in depression (Hill, S. J. et al. Pharmacol. Rev. 1997, 49(3), 253-278). Although H3 receptor antagonists alone may not be capable of increasing serotonin levels in vivo to those required for antidepressant effects, concomitant blockade of the SERT will simultaneously decrease the neuronal reuptake of these neurotransmitter molecules, leading to enhanced concentrations of serotonin in the synaptic cleft and an enhanced therapeutic effect and a potentially reduced side effect profile as compared to a compound with SERT activity alone.
Histamine H3 antagonists have been shown to have pharmacological activity relevant to several key symptoms of depression, including sleep disorders (e.g. sleep disturbances, fatigue, and lethargy) and cognitive difficulties (e.g. memory and concentration impairment), as described above. Therefore, a combined H3/SERT modulating compound would provide symptomatic relief for the sleep disorders, fatigue, and cognitive problems during the first weeks of treatment, before the mood-elevating effect of the SERT modulation is noticed.
Fatigue is a frequent symptom experienced by the more than 340 million people worldwide who are suffering from depression (Jane-Llopis, E.; Hosman, C.; Jenkins, R.; Anderson, P. Br. J. Psychiatry; J. Mental Sci., 2003, 183, 384-397). While antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are frequently able to improve the overall sense of wellbeing for those who use them, these drugs often fail to improve the symptom of fatigue even as mood improves (Nierenberg, A. A.; Keefe, B. R.; Leslie, V. C.; Alpert, J. E.; Pava, J. A.; Worthington, J. J. 3rd; Rosenbaum, J. F.; Fava, M. J. Clin. Psychiatry, 1999, 60, 221-225; Fava, G. A.; Fabbri, S.; Sonino, N. Prog. Neuro-Psychopharmacol. Biol. Psych. 2002, 26, 1019-1027). Some SSRIs even induce fatigue and excessive sleepiness (Beasley, C. M., Jr.; Koke, S. C.; Nilsson, M. E.; Gonzales, J. S. Clin. Ther. 2000, 22, 1319-1330; Zajecka, J. M. J. Clin. Psychiatry, 61 Suppl 2 2000, 20-25).
One possible approach to mitigating the fatigue associated with depression and/or its treatment is through the use of a wake promoting agent. Histamine H3 receptor antagonists are known to increase wakefulness (Monti, J. M.; Jantos, H.; Boussard, M.; Altier, H.; Orellana, C.; Olivera, S. Eur. J. Pharmacol. 1991, 205, 283-287) without showing nonspecific stimulant effects such as increased locomotor activity (Barbier, A. J.; Berridge, C.; Dugovic, C.; Laposky, A. D.; Wilson, S. J.; Boggs, J.; Aluisio, L.; Lord, B.; Mazur, C.; Pudiak, C. M.; Langlois, X.; Xiao, W.; Apodaca, R.; Carruthers, N. I.; Lovenberg, T. W. Br. J. Pharmacol. 2004, 143, 649-661). Thus the case can be made that H3 antagonists would be useful adjuncts to antidepressant therapy.
As part of our strategy for the development of novel approaches to the treatment of depression, we have investigated the possibility of combining histamine H3 antagonism with serotonin transporter (SERT) inhibition in a single chemical entity.
We have recently described several chemical series with high affinities for both targets. Such compounds having H3 receptor activity and SERT activity have been disclosed in U.S. Patent Appl. Publ. Nos. US 2006/0194837 (Aug. 31, 2006), US 2006/0293316 (Dec. 28, 2006), and US 2006/0287292 (Dec. 21, 2006), which are each hereby incorporated by reference. Compounds described herein were discussed by Keith et al. (Bioorg. Med. Chem. Lett. 2007, 17(19), 5325-5329).
However, there remains a need for potent histamine H3 receptor and/or serotonin transporter modulators with desirable pharmaceutical properties. Herein is described the effect of replacing the flexible propyloxypiperidine side chain with a more rigid and polar aromatic spacer.